DESCRIPTION: (Applicant's Abstract) The major objective of this application is to determine whether chemotherapy + liposome-encapsulated MTP-PE (L-MTP- PE), a monocyte/ macrophage activator, improves the metastasis-free survival of newly diagnosed OS patients. A randomized phase III trial will be performed in conjunction with POG and CCSG co- operative groups. The applicant will evaluate the immunomodulatory activity of L-MTP-PE + chemotherapy to determine if certain chemotherapy regimens alter in vivo immune response to L-MTP-PE. The development of pulmonary metastases is a major problem in OS. The 2-yr metastasis-free survival is 65 percent regardless of the chemotherapy regimen employed. More than 50 percent of relapses occur during year 1 while the patients are receiving chemotherapy. No improvements have been made in the past 10 yrs. In a phase II trial with relapsed OS, the applicant has demonstrated the in vivo immunostimulating activity of L-MTP-PE. Circulating TNF, IL-6, IL-8, CRP and neopterin were induced by L-MTP-PE. Unique histologic changes in pulmonary lesions resected after L-MTP-PE therapy were demonstrated and the progression-free interval was significantly increased following 24 wks of L-MTP-PE treatment. A phase IIb trial showed that L-MTP- PE can safely be administered with ifosfamide (IFX) with no increase in IFX toxicity or decrease in immune stimulation. This application is to determine the efficacy of L-MTP-PE + combination chemotherapy in newly diagnosed OS. The applicant's goal is to activate the body's monocytes and pulmonary macrophages to eradicate the residual tumor cells not killed by the chemotherapy. Patients will be randomized to 2 different chemotherapy regimens. A second randomization determines if L-MTP-PE is added to the treatment. This 4-arm study investigates the impact of using L-MTP-PE with different chemotherapy combinations. Patients receive chemotherapy for 10 wks prior to tumor resection then chemotherapy plus or minus L-MTP-PE post operatively. Plasma cytokine levels and monocyte tumoricidal activity will be quantified before and at various times after administration of L-MTP-PE + chemotherapy to determine if certain chemotherapy combinations impair response to L-MTP-PE. The applicant has shown that when patients receive ADR + CTX together, their monocytes were unresponsive to L-MTP-PE in vitro. Therefore, the immunostimulating capacity of L-MTP-PE may be diminished by certain drug combinations which may in turn impact on its effectiveness and ultimately on the success rate of one arm of the trial. Predicting patient outcomes by monitoring monocyte tumoricidal activity is another goal since increased monocyte tumoricidal activity during wk 1 of L-MTP-PE therapy correlated with the clinical response of stage III and IV melanoma patients. Finally, a nude mouse OS model will determine the activity of oral L-MTP-PE. L-MTP-PE is presently given i.v. twice weekly for 36 wks. The ability to give L-MTP-PE orally would greatly reduce the cost and inconvenience of this therapy.